(Abbreviations: LW, Lung Weight; LBWR, Lung to Body weight ratio; DA,
Ductus Arteriosus; RV, right ventricle; TV, tricuspid valve; PA,
Pulmonary valve; LV, Left ventricle)
4.DISCUSSION
4.1. The severity of pulmonary hypoplasia in CDH is inconsistent.
Pulmonary hypoplasia is diagnosed by decreased lung growth and immature
in CDH. It is based on measurement of lung-to-body weight ratio(LBWR)
<0.012 (>28 weeks)2, and the
pathological characteristics are reduced lung parenchyma and terminal
branches of bronchioles, acinar hypoplasia 2. Gas
exchange is impaired severely due to the reduction of alveolar cavity
area and thickening of alveolar walls and
mesenchyme11. Changes in cell phenotype, cell
proliferation, and abnormalities in intercellular signaling pathways
have been identified as potential pathogenic causes in various animal
models of CDH12. In this study, LBWR was lower than
0.012, meanwhile a part of postmortem examination identified lung
development of CDH stagnating at an earlier developmental stage and
presented in the pseudo-glandular or canalicular period, which is
consistent with the clinical GA in diagnosis.
The important finding was that histological manifestations of the lung
were not consistent. The lung development was observed with a relatively
normal performance in ipsilateral lungs or bilateral. Current research
considers the occurrence of CDH to be a dual-hit
hypothesis13. This theory holds that the aberrant lung
developments exist before the diaphragmatic defect occurs, and the
compression secondary to abdominal viscera herniations into the thorax
results inhibition of growth and maturation further. Though this study
has not fully verified this hypothesis. The hit only occurred in the
compression secondary to abdominal viscera herniations, so pulmonary
histological development was close to the normal structure. The
pathogenesis of CDH is complex in person, and the inconsistency reflects
that CDH is a severe disease with strong heterogeneity and evaluating
lung development of infants may provide clearer guidance on the
management of ventilator settings. Given the low sample size present in
this study, we lack statistical significance of predictors for lung
hypoplasia.
It was worth noting that in 7 of the 8 cases received HFOV early after
birth, which was thought to produce less pulmonary
barotrauma14. And because of the continuous
instability of the physiological state, the ventilator support
parameters were adjusted, and the mean MAP increased from 14 to 18
cmH2O. Based on the autopsy reports, severe pulmonary
hemorrhage and hemosiderin deposition in the bilateral lungs and
thickening hyaline membrane formation were found, and atelectasis was
caused by the small number of alveoli and immature structure.
Hyperinflation of the hypoplastic lungs in the ventilation mode of HFOV
aggravated the inflammatory response and leads to lung damage. In
current neonatal practice, mild ventilation and permissive hypercapnia
have become the consensus of ventilator management strategies for
neonates with CDH. However, the appropriate adjustment of ventilator
parameters cannot be performed with minimal but adequate settings for
severe CDH.
4.2 Persistent PH and cardiac dysfunction during fetal-to-neonatal
transition in CDH
While the influence factors of PH have been
described15, it remains challenging to pinpoint
exactly the factors and at which time point are detrimental in leading
to adverse outcome. Elevated right heart pressure, circulatory shunt,
hypoventilation, and decreased systemic function, the sequence of
physiological process in patients with CDH is complex and varies with
the disease severity and progression, which is crucial for guiding
treatment to achieve preoperative stabilization and postoperative
recovery. In our study, all had been proved severe PH with complete or
partial right-to-left shunting across ductus arteriosus, and the ductus
arteriosus median size was approximately 4.6 mm at full autopsy, RV
volume was enlarged, and the thickness of wall was increased. During
fetal cardiopulmonary circulation, pulmonary vascular resistance (PVR)
is high and pulmonary blood flow (PBF) is low because the fetal lung is
not inflated. Thus, most of right ventricular output is shunted from the
ductus arteriosus into the systemic circulation. Left ventricular (LV)
preload is derived from the right-to-left shunting of umbilical venous
blood flow through the foramen ovale16. When umbilical
cord clamping, as the low-resistance placental vascular bed is removed,
loss of umbilical cord venous return reduces LV preload by 30%-50%,
and cardiac output decreases when there is an immediate increase in
systemic vascular resistance17. Pulmonary ventilation
and vasodilation reduce PVR and increase PBF, triggering a transition
from fetal to neonatal circulation. Patients with CDH have lower lung
compliance and delayed lung ventilation due to lung hypoplasia, which
plus a low cardiac index leading to PH18. In the
process of treatment, lung injury aggravated as well as the degree of
respiratory failure, and as hypoxemia and acidosis further stimulate
pulmonary vasospasm, PVR persists increased; while the “vicious
circle” continued to worsen, the clinical condition deteriorated
rapidly. Ultimately, the unstable hemodynamics and rapidity of
deterioration of ventilation contribute to the mismatch between oxygen
supply and demand. In infants with CDH, PVR is often higher than
systemic levels, resulting in extrapulmonary right-to-left shunt and
severe hypoxemia. In autopsy cases, the continuous fetal circulation
could not be improved with severe PH, thereafter, resulting in more
severe right heart failure.
From one of our series, we found the severity of PH and cardiac
dysfunction could be unpredictable and disproportionate to respiratory
status, whose oxygen saturation remained a high level, however, the
patient had severe PDA and died from oliguria. It was also unraveled by
Patel 4,19 et al, holding the view that cardiac
dysfunction may be a more important determinant of disease severity than
PH. Prolonged left-to-right shunting does not further aggravate
pulmonary vasculopathy but is a cause of RV failure20,
and the greater part of the literature ignores the role of PDA and RV
failure in CDH. The timing of drug or surgical ligation of the ductus
arteriosus is less discussed in CDH, which might indicate the future
directions for advancement.
4.3 The pathological manifestations and clinical relationship of
CDH-related PH are still unclear.
The CDH-related PH is
characterized by an interplay of aberrant structural pulmonary
development and postnatal pathologic pulmonary vascular remodeling
caused by hypoxic pulmonary vasoconstriction21. As
acknowledged that histological changes in pulmonary arterioles found in
animal models and human are the processive proliferation of muscular
vascular medial and adventitial layers, decreased vascular branching and
vascular reactivity, as well as reduced lumen
diameter22, however, we found the observed thickening
of the media was in a milder degree than our expectations and the number
of muscular arteries observed microscopically wasn’t decreased.
Enlargement and congestion of capillaries in the alveolar septum and
lung interstitial showed the severity of pulmonary congestion. Among
these cases, pulmonary arteries remained the earliest pathobiological
feature of vascular remodeling but presented a severe clinical
classification. And the effects of pulmonary vasodilators seemed
limited. From our experience, we thought the cardio loading conditions
might have an important impact on the outcomes of the treatment for PH.
The imbalanced of systemic circulation and pulmonary circulation
aggravated the clinical course and the hypoxia pulmonary
vasoconstriction impacted less. Based on our small observational study,
the view needs further in-depth research.
5.CONCLUSION
In conclusion, the pathological changes of CDH can lead to better
introspection by the clinical team. In this study, histopathological
findings highlighted that ipsilateral pulmonary structure may be normal
despite the reduced volume; it was also noteworthy the pulmonary hyaline
membrane formation and diffuse hemorrhage indicated unignorable lung
damages.
Modern therapy of the respiratory management still should be improved
based on lung protection strategies to avoid barotrauma and atelectasis.
A vicious circle of lung hypoplasia combined with severe PH and RV
failure contributory to refractory hypoxemia are major fatal factors
among our series. The management of severe CDH should focus on the
timely correction for vicious circle of persistent PH, which is based on
the physiological PH in perinatal transition and synergy with giant
PDAs; Medications targeted pulmonary vascular lesions strives to
transfer to more personalized ways from the single drug-use pattern. Aim
to improve oxygenation and minimize cardiopulmonary symptoms, pulmonary
vasodilators, gentle ventilation, fluid resuscitation, and hemodynamic
homeostasis need mutual coordination. In addition, collecting CDH tissue
to establish a biological sample bank, and further translational
research can propose new
possibilities for clinical treatment.
ACKNOWLEDGMENTS
This study was supported by the Pediatric Medical Coordinated
Development Center of Beijing Hospitals Authority(XTZD20180305 to
Li-Shuang Ma);Foundation project of Beijing Research Association for
Chronic Disease Prevention and Health Education in
2022(BJMB0012022028001 to Li-Shuang Ma)
CONFLICT OF INTERESTS
The authors declare that there are no conflicts of interests.
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